Amyotrophic Lateral Sclerosis€¦ · right calf and hyperreflexia of the right biceps and of deep...

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 377;2 nejm.org July 13, 2017162

Review Article

From the Department of Neurology, Uni-versity of Massachusetts Medical School, Worcester (R.H.B.); and the Maurice Wohl Clinical Neuroscience Institute, De-partment of Basic and Clinical Neuro-science, King’s College London, London (A.A.-C.). Address reprint requests to Dr. Brown at the Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655, or at robert . brown@ umassmed . edu.

N Engl J Med 2017;377:162-72.

DOI: 10.1056/NEJMra1603471

Copyright © 2017 Massachusetts Medical Society.

Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic

disorder characterized by degeneration of motor neurons in the brain and

spinal cord. It begins insidiously with focal weakness but spreads relent-

lessly to involve most muscles, including the diaphragm. Typically, death due to

respiratory paralysis occurs in 3 to 5 years.

Motor neurons are grouped into upper populations in the motor cortex and

lower populations in the brain stem and spinal cord; lower motor neurons inner-

vate muscle (Fig. 1). When corticospinal (upper) motor neurons fail, muscle stiff-

ness and spasticity result. When lower motor neurons become affected, they ini-

tially show excessive electrical irritability, leading to spontaneous muscle twitching

(fasciculations); as they degenerate, they lose synaptic connectivity with their target

muscles, which then atrophy.

ALS typically begins in the limbs, but about one third of cases are bulbar, heralded

by difficulty chewing, speaking, or swallowing. Until late in the disease, ALS

spares neurons that innervate the eye and sphincter muscles. The diagnosis is

based primarily on clinical examination in conjunction with electromyography, to

confirm the extent of denervation, and laboratory testing, to rule out reversible

disorders that may resemble ALS.1,2

A representative case involves a 55-year-old patient who was evaluated for foot

drop, which had begun subtly 4 months earlier with the onset of muscle cramping

in the right calf as a result of volitional movement (known as volitional cramping)

and had progressed to severe weakness of ankle dorsiflexion and knee extension.

In addition to these features, the physical examination revealed atrophy of the

right calf and hyperreflexia of the right biceps and of deep tendon reflexes at both

knees and both ankles. The neurologic examination was otherwise normal. Elec-

tromyography showed evidence of acute muscle denervation (fibrillations) in all

four limbs and muscle reinnervation in the right calf (high-amplitude compound

muscle action potentials). Imaging of the head and neck revealed no structural

lesions impinging on motor tracts, and the results of laboratory studies were nor-

mal, findings that ruled out several disorders in the differential diagnosis, such as

peripheral neuropathy, Lyme disease, vitamin B12 deficiency, thyroid disease, and

metal toxicity.3 A full evaluation disclosed no evidence of a reversible motor neuron

disorder, such as multifocal motor neuropathy with conduction block, which is

typically associated with autoantibodies (e.g., anti-GM1 ganglioside antibodies)

and can be effectively treated with intravenous immune globulin.4

The clinical presentation of ALS is heterogeneous with respect to the popula-

tions of involved motor neurons and survival (Fig. 2).2 When there is prominent

involvement of frontopontine motor neurons that serve bulbar functions, a strik-

ing finding is emotional lability, indicating pseudobulbar palsy, which is charac-

terized by facial spasticity and a tendency to laugh or cry excessively in response

to minor emotional stimuli.

Dan L. Longo, M.D., Editor

Amyotrophic Lateral Sclerosis

Robert H. Brown, D.Phil., M.D., and Ammar Al-Chalabi, Ph.D., F.R.C.P., Dip.Stat.

The New England Journal of Medicine Downloaded from nejm.org at KINGS COLLEGE LONDON on July 15, 2017. For personal use only. No other uses without permission.

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

n engl j med 377;2 nejm.org July 13, 2017 163

Amyotrophic Later al Sclerosis

In primary lateral sclerosis, there is selective

involvement of corticospinal and corticopontine

motor neurons, with few findings of lower motor

neuron dysfunction.5 Primary lateral sclerosis is

ruled out in the representative case described

above because of the atrophy and electromyo-

graphic findings, which are indicative of lower

motor neuron disease. Primary lateral sclerosis

progresses slowly, with severe spastic muscle

stiffness and little muscle atrophy. This disorder

overlaps clinically with a broad category of corti-

cospinal disorders designated as hereditary spas-

tic paraplegias, which are typically symmetrical

in onset, slowly progressive, and sometimes asso-

ciated with sensory loss and other multisystem

findings. In primary lateral sclerosis but not

hereditary spastic paraplegias, bulbar involve-

ment may be prominent. In progressive muscu-

lar atrophy, lower motor neuron involvement is

predominant, with little spasticity. The hyperre-

flexia in the representative case is inconsistent

with progressive muscular atrophy.

During the past two decades, it has been recog-

nized that 15 to 20% of persons with ALS have

progressive cognitive abnormalities marked by

behavioral changes, leading ultimately to de-

mentia.6 Since these behavioral alterations corre-

late with autopsy evidence of degeneration of the

frontal and temporal lobes, the condition is des-

ignated frontotemporal dementia. It was formerly

called Pick’s disease.

Epidemiol o gic Fe at ur es

In Europe and the United States, there are 1 or

2 new cases of ALS per year per 100,000 people;

the total number of cases is approximately 3 to

5 per 100,000.7,8 These statistics are globally fairly

uniform, although there are rare foci in which

ALS is more common. The incidence and preva-

lence of ALS increase with age. In the United

States and Europe, the cumulative lifetime risk

of ALS is about 1 in 400; in the United States

alone, 800,000 persons who are now alive are

expected to die from ALS.9 About 10% of ALS

cases are familial, usually inherited as dominant

traits.10 The remaining 90% of cases of ALS are

sporadic (occurring without a family history). In

cases of sporadic ALS, the ratio of affected

males to affected females may approach 2:1; in

familial ALS, the ratio is closer to 1:1. ALS is the

most frequent neurodegenerative disorder of

midlife, with an onset in the middle-to-late 50s.

An onset in the late teenage or early adult years

is usually indicative of familial ALS. The time

Figure 1. The Motor System.

The motor system is composed of corticospinal (upper) motor neurons

in the motor cortex and bulbar and spinal (lower) motor neurons, which

innervate skeletal muscle.

UPPER MOTORNEURONS

Medulla

Right motorcortex

CervicalSpinal Cord

Lateralcorticospinal tract

Corticospinaltract

Anterior corticospinal tract

ThoracicSpinal Cord

LumbarSpinal Cord

Limb muscle

Somatic motorneuron

Bulbar motorneuron

Oropharyngealmuscle

LOWER MOTORNEURONS





from the first symptom of ALS to diagnosis is

approximately 12 months, a problematic delay if

successful therapy requires early intervention.

Because an abundance of ALS genes have now

been identified, it will probably be informative

to reanalyze this epidemiologic profile of ALS

with stratification according to genetically de-

fined subtypes.

Pathol o gic a l Ch a r ac ter is tics

The core pathological finding in ALS is motor

neuron death in the motor cortex and spinal

cord; in ALS with frontotemporal dementia,

neuronal degeneration is more widespread, oc-

curring throughout the frontal and temporal

lobes. Degeneration of the corticospinal axons

causes thinning and scarring (sclerosis) of the

lateral aspects of the spinal cord. In addition, as

the brain stem and spinal motor neurons die,

there is thinning of the ventral roots and dener-

vational atrophy (amyotrophy) of the muscles of

the tongue, oropharynx, and limbs. Until late in

the disease, ALS does not affect neurons that

innervate eye muscles or the bladder. Degenera-

tion of motor neurons is accompanied by neuro-

inflammatory processes, with proliferation of

astroglia, microglia, and oligodendroglial cells.11,12

A common feature in cases of both familial and

sporadic ALS is aggregation of cytoplasmic pro-

teins, prominently but not exclusively in motor

neurons. Some of these proteins are common in

most types of ALS. This is exemplified by the

nuclear TAR DNA-binding protein 43 (TDP-43),

which in many cases of ALS is cleaved, hyper-

phosphorylated, and mislocalized to the cyto-

plasm.13 Aggregates of ubiquilin 2 are also

common,14 as are intracytoplasmic deposits of

wild-type superoxide dismutase 1 (SOD1) in spo-

radic ALS.15 Many protein deposits show evi-

dence of ubiquitination; threads of ubiquitinated

TDP-43 are prominent in motor neurons, both

terminally and before atrophy of the cell body.

Given the diverse causes of ALS, it is not surpris-

ing that some types of aggregates are detected

only in specific ALS subtypes (e.g., dipeptide

aggregates and intranuclear RNA deposits in

C9ORF72 ALS).

Gene tic Fe at ur es

Evolving technologies for gene mapping and

DNA analysis have facilitated the identification

of multiple ALS genes (Fig. 3). SOD1 was the first

ALS gene to be identified, in 1993.16 More than

120 genetic variants have been associated with a

risk of ALS17 (http://alsod . iop . kcl . ac . uk). Several

criteria assist in identifying those that are most

meaningful. The strongest confirmation is vali-

dation in multiple independent families and co-

horts. Also supportive are an increased burden

of the variant in cases relative to controls and

the predicted consequences of the variant (e.g.,

missense mutation vs. truncation). It has proved

almost impossible to predict a variant’s rele-

vance to ALS from the biologic features of the

gene itself. As shown in Figure 3, at least 25

Figure 2. Phenotype and Survival in Amyotrophic Lateral Sclerosis (ALS).

Panel A shows survival curves for two types of ALS (spinal-onset and bulbar-

onset) and two other motor neuron diseases (primary lateral sclerosis and

progressive muscular atrophy). Panel B shows lateral atrophy and furrow-

ing of the tongue in a patient with ALS, findings that reflect denervation

due to degeneration of bulbar motor neurons. Panel C shows thinned arms

and shoulders, findings that are typical of the flail-arm syndrome, which

occurs in patients with ALS and is associated with protracted survival.

A

B C

Pro

po

rtio

n o

f P

atie

nts

Aliv

e

1.0

0.6

0.8

0.4

0.2

0.00 100 200 300 400 500

Survival from Onset (mo)

Primary lateral sclerosis

Progressive muscular atrophy

Spinal-onset ALS

Bulbar-onset ALS





genes have now been reproducibly implicated in

familial ALS, sporadic ALS, or both.18-20

A by-product of the genetic studies that is

highly relevant to therapeutic development has

been the generation of mouse models of ALS.

Strikingly, transgenic expression of mutant SOD1

protein21 and, more recently, profilin 1 (PFN1)22

generates a neurodegenerative, paralytic process

in mice that mimics many aspects of human

ALS. An important lesson from transgenic mod-

els of TDP-43 and FUS (fused in sarcoma) is that

levels of the normal protein are tightly con-

trolled. In contrast with SOD1, forced expression

of high levels of normal TDP-43 by itself triggers

motor neuron degeneration.23 Mouse models of

C9orf72 (the 72nd open reading frame identified

on chromosome 9, the most commonly mutated

gene in ALS) have now also been generated for

C9ORF72 ALS and are discussed below.

Correlations between genetic variants and

different clinical profiles in ALS, such as age at

onset, disease duration, and site of onset, have

been defined (Table 1). An important example is

the gene that encodes the enzyme ephrin A4

(EPHA4)33 — lower levels of expression of EPHA4

correlate with longer survival. Some genetic vari-

ants influence both susceptibility and phenotype.

For example, progression is accelerated in pa-

tients with the common A4V mutation30 of SOD1

and in patients with the P525L mutation of FUS/

TLS; the latter may lead to fulminant, childhood-

onset motor neuron disease.28

Concep t s in Patho genesis

A comprehensive explanation for ALS must in-

clude both its familial and sporadic forms, as well

as categories of phenotypic divergence that arise

even with the same proximal trigger, such as a

gene mutation. A general presumption has been

that the disease reflects an adverse interplay

between genetic and environmental factors. An

alternative view postulates that all cases of ALS

are a consequence primarily of complex genetic

factors. Several perspectives suggest that the

pathogenesis of ALS entails a multistep process.34

Lessons from Familial ALS

There is striking heterogeneity in the genetic

causes of familial ALS, but familial ALS and

sporadic ALS have similarities in their patho-

logical features, as well as in their clinical fea-

tures, suggesting a convergence of the cellular

and molecular events that lead to motor neuron

degeneration. These points of convergence de-

fine targets for therapy.

A working view of the present panel of ALS

genes is that they cluster in three categories,19

involving protein homeostasis, RNA homeosta-

sis and trafficking, and cytoskeletal dynamics

(Fig. 4). These mechanisms are not exclusive. For

example, protein aggregates may sequester pro-

teins that are important in RNA binding, thereby

perturbing RNA trafficking and homeostasis.

Moreover, these mechanisms are detected in the

context of both familial ALS and sporadic ALS;

some nonmutant proteins also have a propensity

to misfold and aggregate in ALS, much like their

mutant counterparts (e.g., SOD1 and TDP-43).

Downstream of each category are diverse

forms of cellular abnormalities, including the

deposition of intranuclear and cytosolic protein

and RNA aggregates, disturbances of protein

degradative mechanisms, mitochondrial dysfunc-

tion, endoplasmic reticulum stress, defective

nucleocytoplasmic trafficking, altered neuro-

nal excitability, and altered axonal transport.

In most cases, these events activate and recruit

nonneuronal cells (astrocytes, microglia, and

oligodendroglia), which exert both salutary and

Figure 3. ALS Gene Discovery since 1990.

The cumulative numbers of known ALS genes have increased rapidly. The

size of each circle reflects the proportion of all familial ALS cases associat-

ed with that gene (e.g., 20% for SOD1 and 45% for C9ORF72). Blue circles

indicate genes associated only with familial ALS, red circles indicate genes

associated only with sporadic ALS, and circles that are half blue and half

red indicate genes associated with both familial and sporadic ALS. Each of

these genes has been found to be mutated in more than one ALS-affected

family or in multiple, unrelated cases of sporadic ALS.

Gen

e C

ou

nt

30

20

25

15

10

5

1995 2000 2005 2010 2015 2020

Year of Discovery

01990

SOD1

ANGVAPB

SQSTM1DCTN1

FUSUNC13A

ATXN2

C9ORF72

HNRNPA1CHCHD10

SCFD1

MOBP

C21ORF2NEK1

VCPTARDBP

DAO

TAF15OPTN

UBQLN2 PFN1

MATR3TBK1

TUBA4A

Implicated in protein homeostasis

Involved in altered RNA-binding proteins

Involved in cytoskeletal proteins





negative influences on motor neuron viability.

The diverse downstream abnormalities may

differentially affect subcellular compartments

(dendrites, soma, axons, and neuromuscular

junctions). One implication of this model is that

successful therapy for ALS will require simulta-

neous interventions in multiple downstream

pathways.

Genes That Influence Protein Homoeostasis

The most extensively investigated pathological

finding in ALS has been the accumulation of

aggregated proteins and corresponding defects

in the cellular pathways for protein degradation.

Mutant SOD1 frequently forms intracellular ag-

gregates. Genes that encode adapter proteins in-

volved in protein maintenance and degradation

are also implicated in ALS. These include valo-

sin-containing protein (VCP)35 and the proteins

optineurin (OPTN),36 TANK-binding kinase 1

(TBK1),37-39 and sequestosome 1 (SQSTM1/p62)40

(Fig. 4A). The TBK1–OPTN axis is interwoven in

other neurodegenerative disorders; for example,

the Parkinson’s disease gene PINK1 encodes a

protein that acts upstream of TBK1 in the mobi-

lization of mitophagy.

Genes That Influence RNA Homeostasis

and Trafficking

The most rapidly expanding category of ALS

genes encodes proteins that interact with RNA.

The first protein to be discovered was TDP-43,13

whose mislocalization from the nucleus to the

cytosol, cleavage, phosphorylation, and ubiquiti-

nation were initially illuminated in sporadic ALS

and frontotemporal dementia. However, it be-

came apparent that mutations in TARDBP, the

gene encoding TDP-43, can cause familial ALS.41

Mislocalization and post-translational modifica-

tion of TDP-43 are observed in many neurode-

GeneMinor Allele Frequency or

Expression Level Phenotype Study

Site of OnsetEffect of Minor Allele

on Age at Onset*Effect of Minor

Allele on Survival†

Genomewide association study

rs3011225-1p34 0.22 2 yr later Ahmeti et al.24

UNC13A 0.40 Shorter by 5–10 mo Diekstra et al.25

CAMTA1 0.26 Shorter by about 5 mo

Fogh et al.26

IDE 0.03 Shorter by about 7 mo

Fogh et al.26

Known ALS genes

C9ORF72 Up to 0.08 Primarily bulbar Cooper-Knock et al.27

FUS-P525L Rare variation Many years earlier Shorter by several months

Conte et al.28

PFN1 Rare variation Limb Wu et al.29

SOD1-A4V Rare variation Limb Shorter by several months

Cudkowicz et al.30

SOD1/SOD1 Rare variation Many years earlier Shorter by several months

Winter et al.31

Modifier genes

APOE Expression increased Longer by several months

Lacomblez et al.32

EPHA4 Expression decreased Longer by several months

Van Hoecke et al.33

* The effect of the minor allele on age is shown relative to a cohort with the major allele.† The effect of the minor allele on survival is shown relative to a cohort with the major allele.

Table 1. Genetic Variants That Influence the Phenotype in Amyotrophic Lateral Sclerosis.




167


generative diseases. FUS-TLS encodes another

RNA-binding protein, homologous to TDP-43,

which in mutant form also causes ALS.42,43 Why

mutated genes encoding RNA-binding proteins

cause ALS is not clear. These proteins have

multiple functions in gene splicing, surveil-

lance of transcripts after splicing, generation of

microRNA, and axonal biologic processes. Most

of these proteins have low-complexity domains

that permit promiscuous binding not only to

RNA but also to other proteins. The ALS-related

mutations heighten this binding propensity,

leading to self-assembly of the proteins and the

formation of aggregates.44 This auto-aggregation

is facilitated in stress granules, which are non–

membrane-bound structures formed under cell

stress that contain RNA complexes stalled in

translation.45-47 The self-assembly of mutant RNA-

binding proteins may induce toxic, self-propagat-

ing conformations that disseminate disease with-

in and between cells in a manner analogous to

that of prion proteins.

The most commonly mutated gene in ALS is

C9ORF72.48-50 The C9ORF72 protein has a role in

nuclear and endosomal membrane trafficking

and autophagy. A noncoding stretch of six nucle-

otides is repeated up to approximately 30 times

in normal persons. Expansions of this segment

to hundreds or thousands of repeats cause famil-

ial ALS and frontotemporal dementia; in addition,

these expansions sometimes cause sporadic ALS.

Several mechanisms may contribute to the neuro-

toxicity of the hexanucleotide expansion (Fig. 4B).

Transcripts of the offending segments are de-

posited in the nucleus, forming RNA foci that

sequester nuclear proteins. Some of the expand-

ed RNA escapes to the cytoplasm, where it gen-

erates five potentially toxic repeat dipeptides

through a noncanonical translation process.

Recent studies have also shown a defect in trans-

port across the nuclear membrane in cells with

the C9ORF72 expansions.51,52 A reduction in the

total levels of the normal C9ORF72 protein may

also contribute to neurotoxicity.53-55 Transgenic

mouse models of C9orf72 recapitulate the molecu-

lar features of C9ORF72 ALS in humans56-59 but,

with one exception,59 do not show a strong mo-

tor phenotype.

Genes That Influence Cytoskeletal Dynamics

Three ALS genes encode proteins that are im-

portant in maintenance of normal cytoskeletal

dynamics: dynactin 1 (DCTN1),60 PFN1,29 and

tubulin 4A (TUBA4A) (Fig. 4C).61 TUBA4A dimers

are components of microtubules, whose integ-

rity is essential for axonal structure; DCTN1 is

implicated in retrograde axonal transport, where-

as PFN1 participates in the conversion of globu-

lar to filamentous actin and nerve extension.

Also implicated is the modifier gene EPHA4;

lower levels of EPHA4 expression correlate with

longer survival in ALS, perhaps because they

permit more exuberant axonal extension.

Insights into Sporadic ALS

Despite the absence of a family history in spo-

radic ALS, studies involving twins show that the

heritability is about 60%.62 Furthermore, muta-

tions usually found in familial ALS can be found

in sporadic ALS. This can be partly explained by

the difficulty in ascertaining whether patients

with late-onset disease have a family history of

ALS. The situation is confounded by the observa-

tion that some familial ALS gene variants increase

the risk of phenotypes other than ALS, such as

frontotemporal dementia.38,39,48 Unless these other

phenotypes are recognized as relevant, the fam-

ily history may be incorrectly recorded as nega-

tive. In addition, several familial ALS gene vari-

ants are of intermediate penetrance (e.g., the

C9ORF72 hexanucleotide repeat expansion, ATXN2

repeat expansions,63 and TBK1 mutations).37-39

Thus, ALS might not be manifested in a gene

carrier, in which case, the disease is character-

ized by familial clustering rather than mendelian

inheritance and may appear to be sporadic.64

Combinations of such gene variants further in-

crease the risk of ALS and may be another cause

of apparently sporadic ALS.65

Recent genomewide association studies have

shown that rare genetic variation is dispropor-

tionately frequent in sporadic ALS.66 The genetic

architecture of sporadic ALS is markedly differ-

ent from that of complex diseases such as

schizophrenia in which there are additive effects

of hundreds of common variants, each with a

minute effect on risk. However, common vari-

ants still have a part to play in sporadic ALS. For

example, variants in the genes UNC13A, MOBP,

and SCFD1 all increase the risk by a small but

significant degree.66

Heritability studies also show that a substan-

tial fraction of cases of sporadic ALS cannot be

attributed to genetic or biologic factors; these





cases are ascribed to environmental or undefined

factors. Attempts to identify occupations or

common exposures that might increase the risk

of ALS have been inconclusive. Environmental

studies are challenging because the number of

possible exposures is large, and a critical, dis-

ease-related exposure may have happened many

years before the onset of the disease. A particu-

lar difficulty is that studies of ALS are suscep-

tible to bias because of the poor prognosis. Pa-

tients who live long enough to attend a specialist

research clinic are different from those identi-

fied in population studies, and this difference

can cause bias in the results. For instance, smok-

IntranuclearRNA loci

N U C L E U S

N U C L E U S

FUSTDP-43HNRNPA2ATXN2

Enhanced growthcone expansion

↓ EPHA4

GGGGCCGGGGCC GGGGCC GGGGCC GGGGCC

A

SOD1

UBQLN2VAPB

TBK1OPTNSQSTM1/p62

NF-κBInterferon-βTNF-α

B

C

Aggregates ofmisfolded or

mutant protein

Section of C9ORF72 geneHaploinsufficiency

and lossof function

Repeat-associated non-AUG(RAN) translation initiation

Dipeptiderepeat proteins

RNA-binding proteinsequestrationHexanucleotide expansion from

20 to 30 repeats to hundreds ofrepeats in mutated C9ORF72

Vesicle

Microtubule

Axon

Lysosome

Autophagosome

Autolysosome

Endoplasmicreticulum

ERAD

Prion-like self-assembly and propagation

Autophagy andmitophagy

Gain ofFunction

Loss ofFunction

Neuroinflammation

Neurotoxicity and motor neuron

degeneration

RNA- andprotein-mediated

neurotoxicity

Impaired growthcone expansion

Abnormalaxonal transport

Impaired axonalstability

Perturbations ofgene splicing

Impaired nuclearmembrane transport

Normal alleleHalf the amount of

normal C9ORF72 protein

MutantC9ORF72

protein

Mutated allele withhexanucleotide

expansionChromosome 9

Proteasome

S T R E S SG R A N U L E

G R O W T H C O N E

DCTN1

TUBA4A

↑ EPHA4

Profilin 1

Depolymerizingmicrotubule

DyneinDynactin

Cargo

Microtubule

GrowingF-actin segment

ADP-actin

ADPSlowedbinding ATP

ATP-actin

VCP

Ataxin





ing has been shown to shorten survival in a

population study,67 so a case–control study select-

ing participants from clinics would find smok-

ers underrepresented in the ALS group and

would thus suggest that smoking either has no

effect or might be protective. Similarly, ALS spe-

cialists report anecdotally that their patients tend

to be athletic, slim, and very fit,68 but if these

factors slow disease progression rather than in-

crease risk, such patients will be overrepresented

at specialist centers.

Notwithstanding the barriers to identifying

environmental risk factors, some factors have

been associated with ALS in multiple studies.69,70

The exposure with the strongest support is mili-

tary service.71,72 In addition, smoking has been

implicated as a dose-dependent risk factor for

ALS.73 Exposure to heavy metals may be impor-

tant; blood lead levels and cerebrospinal fluid

manganese levels are higher in patients with

ALS than in controls.70 People with occupations

involving exposure to electromagnetic fields also

appear to be at increased risk, but people living

near power lines are not. Other risk factors with

varying levels of support include pesticide expo-

sure and neurotoxins such as those produced by

cyanobacteria. Viruses have been studied as a

possible explanation for sporadic ALS. Initial

studies suggesting the role of an activated, endog-

enous retrovirus74 were followed by the identifi-

cation of a possible candidate, human endoge-

nous retrovirus K.75

There is increasing evidence that trauma pre-

cedes some individual cases of ALS.76 A meta-

analysis has suggested that trauma overall,

trauma occurring more than 5 years previously,

bone fracture, and head injury are all associated

with an increased risk.77 In recent years, it has

been observed that persons engaged in sports

that entail repetitive concussions or subconcus-

sive head trauma are at increased risk for ALS

and a concurrent behavioral disorder marked by

impulsivity and memory loss. Autopsy studies in

persons with this disorder, called chronic trau-

matic encephalopathy, have revealed fronto-

temporal atrophy associated with distinctive

deposits of tau protein, as well as TDP-43, the

characteristic inclusion protein in ALS.78

Ther a peu tics a nd Be yond

No therapy offers a substantial clinical benefit

for patients with ALS. The drugs riluzole79 and

edaravone, which have been approved by the

Food and Drug Administration for the treatment

of ALS, provide a limited improvement in surviv-

al. Riluzole acts by suppressing excessive motor

neuron firing, and edaravone by suppressing

oxidative stress. Numerous other compounds

that have been investigated have not been shown

to be effective.80,81 Currently, the mainstay of

care for patients with ALS is timely intervention

to manage symptoms, including use of nasogas-

tric feeding, prevention of aspiration (control of

salivary secretions and use of cough-assist de-

vices), and provision of ventilatory support (usu-

ally with bilevel positive airway pressure). Some

interventions raise serious ethical issues, such as

whether to perform tracheostomy for full venti-

lation and, if so, when and how to withdraw

respiratory support once it has been instituted.

Despite the pipeline of potential treatments

for ALS, reflecting the expanded list of targets

Figure 4 (facing page). Three Major Categories

of Pathophysiological Processes in ALS.

The pathways relating the implicated proteins (red)

and key cellular structures and molecules (gray) are

shown. Downstream dysfunctional events are black

within gray boxes. Panel A shows altered protein ho-

meostasis in ALS. Many ALS genes encode adapter

proteins that are critical in protein degradation, acting

at the level of the endoplasmic reticulum (endoplas-

mic reticulum–associated protein degradation [ERAD])

and through proteosomal and autophagic pathways.

RNA-binding proteins may self-assemble to form pri-

on-like aggregates. Panel B shows mechanisms of

C9ORF72-related disease. The toxicity of expanded

hexanucleotide repeats in the C9ORF72 gene is pro-

posed to involve depositions of intranuclear RNA, with

resulting perturbations of gene splicing and sequestra-

tion of RNA-binding proteins; noncanonical translation

of polydipeptides from the expanded DNA, yielding toxic

repeat dipeptides; disturbances of nucleocytoplasmic

transport; and reduced levels of C9ORF72 (haploinsuf-

ficiency). Panel C shows altered neuronal cytoskeletal

dynamics in ALS. Genes encoding dynactin (DCTN1)

and tubulin 4A (TUBA4A) are essential in the mainte-

nance of the structure of the motor nerve axon; muta-

tions in these genes disturb both axonal integrity and

axonal transport. Profilin 1 (PFN1) is essential for the

assembly of filamentous axons and the formation of

distal axonal growth cones. PFN1 mutations and in-

creased expression of ephrin A4 (EPHA4) slow the ex-

tension of the distal axon. ADP denotes adenosine di-

phosphate, NF-κB nuclear factor kappa light-chain

enhancer of activated B cells, and TNF tumor necrosis

factor.





identified through genetic studies and increas-

ing numbers of ALS investigators, many of whom

are in the pharmaceutical sector,80,82 no drugs

are being investigated in late-phase clinical trials.

Several innovative approaches to treating ALS

(and other neurodegenerative diseases) are in

development. Two examples include the use of

adeno-associated viruses (AAV) to achieve wide-

spread delivery of diverse cargoes (missing genes,

therapeutic genes, or gene-silencing elements) to

the central nervous system and the use of stem

cells that provide neurotrophic factors to the

central nervous system.83 Studies in cells, mice,

and humans support the view that several types

of reagents (e.g., antisense oligonucleotides and

AAV-delivered microRNA) inactivate production

of toxic gene products and thus may be thera-

peutic in ALS mediated by genes such as SOD184-87

and C9ORF72. Indeed, clinical trials investigating

the use of antisense oligonucleotides to silence

SOD1 have begun.

One can anticipate continued progress in

understanding the biology of ALS. There is no

doubt that high-throughput genetics, combined

with improved clinical phenotyping, will further

refine the genetic landscape of ALS. As thou-

sands of full genome sequences become avail-

able, it will be feasible to explore the possibility

that complex interactions among multiple gene

variants explain not only familial ALS but also

sporadic ALS. The exploration of environmental

factors in sporadic ALS will expand, with a

focus on the internal environment represented

by the microbiome. The ultimate proof of our

understanding of the biology of ALS will hinge

on our ability to modify the clinical course of

the disease.

Dr. Brown reports holding equity in AviTx, Amylyx Pharma-

ceuticals, and ImStar Therapeutics, receiving fees for serving on

an advisory board from Voyager Therapeutics, negotiating a col-

laborative agreement with WAVE Biosciences, holding patents

and receiving royalties for patents on “Method for the diagnosis

of familial amyotrophic lateral sclerosis” (US 5,843,641) and

“Mice having a mutant SOD1 encoding transgene” (US 6,723,893),

holding a patent for “Compounds and method for the diagnosis,

treatment and prevention of cell death” (US 5,849,290), and

holding a pending patent for “Use of synthetic microRNA for

AAV-mediated silencing of SOD1 in ALS”; and Dr. Al-Chalabi

reports receiving consulting fees from GlaxoSmithKline, pro-

viding unpaid consulting for Mitsubishi Tanabe Pharma, Tree-

way, Chronos Therapeutics, and Avanir Pharmaceuticals, receiv-

ing consulting fees and serving as principal investigator in an

international commercial clinical trial of tirasemtiv in ALS for

Cytokinetics, and serving as chief investigator of an interna-

tional commercial clinical trial of levosimendan in ALS for Ori-

on Pharma. No other potential conflict of interest relevant to

this article was reported.

Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

References

1 . Rowland LP, Shneider NA. Amyo-

trophic lateral sclerosis. N Engl J Med

2001; 344: 1688-700.

2 . Al-Chalabi A, Hardiman O, Kiernan

MC, Chiò A, Rix-Brooks B, van den Berg

LH. Amyotrophic lateral sclerosis: mov-

ing towards a new classification system.

Lancet Neurol 2016; 15: 1182-94.

3 . Rezania K, Roos RP. Spinal cord: mo-

tor neuron diseases. Neurol Clin 2013; 31:

219-39.

4 . Arcila-Londono X, Lewis RA. Multifo-

cal motor neuropathy. Handb Clin Neurol

2013; 115: 429-42.

5 . Gordon PH, Cheng B, Katz IB, et al.

The natural history of primary lateral

sclerosis. Neurology 2006; 66: 647-53.

6 . Bang J, Spina S, Miller BL. Frontotem-

poral dementia. Lancet 2015; 386: 1672-82.

7 . Robberecht W, Philips T. The chang-

ing scene of amyotrophic lateral sclerosis.

Nat Rev Neurosci 2013; 14: 248-64.

8 . Chiò A, Logroscino G, Traynor BJ,

et al. Global epidemiology of amyotrophic

lateral sclerosis: a systematic review of

the published literature. Neuroepidemiol-

ogy 2013; 41: 118-30.

9 . Johnston CA, Stanton BR, Turner MR,

et al. Amyotrophic lateral sclerosis in an

urban setting: a population based study

of inner city London. J Neurol 2006; 253:

1642-3.

1 0 . Mulder DW, Kurland LT, Offord KP,

Beard CM. Familial adult motor neuron

disease: amyotrophic lateral sclerosis.

Neurology 1986; 36: 511-7.

1 1 . Philips T, Rothstein JD. Glial cells in

amyotrophic lateral sclerosis. Exp Neurol

2014; 262 Pt B: 111-20.

1 2 . Kang SH, Li Y, Fukaya M, et al. Degen-

eration and impaired regeneration of gray

matter oligodendrocytes in amyotrophic

lateral sclerosis. Nat Neurosci 2013; 16:

571-9.

1 3 . Neumann M, Sampathu DM, Kwong

LK, et al. Ubiquitinated TDP-43 in fronto-

temporal lobar degeneration and amyo-

trophic lateral sclerosis. Science 2006;

314: 130-3.

1 4 . Deng HX, Chen W, Hong ST, et al.

Mutations in UBQLN2 cause dominant X-

linked juvenile and adult-onset ALS and

ALS/dementia. Nature 2011; 477: 211-5.

1 5 . Bosco DA, Morfini G, Karabacak NM,

et al. Wild-type and mutant SOD1 share

an aberrant conformation and a common

pathogenic pathway in ALS. Nat Neurosci

2010; 13: 1396-403.

1 6 . Rosen DR, Siddique T, Patterson D,

et al. Mutations in Cu/Zn superoxide dis-

mutase gene are associated with familial

amyotrophic lateral sclerosis. Nature 1993;

362: 59-62.

1 7 . Taylor JP, Brown RH Jr, Cleveland DW.

Decoding ALS: from genes to mechanism.

Nature 2016; 539: 197-206.

1 8 . Therrien M, Dion PA, Rouleau GA.

ALS: recent developments from genetics

studies. Curr Neurol Neurosci Rep 2016;

16: 59-71.

1 9 . Peters OM, Ghasemi M, Brown RH Jr.

Emerging mechanisms of molecular pa-

thology in ALS. J Clin Invest 2015; 125:

2548.

2 0 . Pottier C, Ravenscroft TA, Sanchez-

Contreras M, Rademakers R. Genetics of

FTLD: overview and what else we can ex-

pect from genetic studies. J Neurochem

2016; 138: Suppl 1: 32-53.

2 1 . Gurney ME, Pu H, Chiu AY, et al.

Motor neuron degeneration in mice that ex-

press a human Cu,Zn superoxide dismutase

mutation. Science 1994; 264: 1772-5.

2 2 . Yang C, Danielson EW, Qiao T, et al.

Mutant PFN1 causes ALS phenotypes and

progressive motor neuron degeneration

in mice by a gain of toxicity. Proc Natl

Acad Sci U S A 2016; 113: E6209-E6218.

2 3 . Mitchell JC, Constable R, So E, et al.

Wild type human TDP-43 potentiates ALS-





linked mutant TDP-43 driven progressive

motor and cortical neuron degeneration

with pathological features of ALS. Acta

Neuropathol Commun 2015; 3: 36.

24. Ahmeti KB, Ajroud-Driss S, Al-Chalabi

A, et al. Age of onset of amyotrophic

lateral sclerosis is modulated by a locus

on 1p34.1. Neurobiol Aging 2013; 34(1):

357.e7-19.

25. Diekstra FP, Van Deerlin VM, van

Swieten JC, et al. C9orf72 and UNC13A

are shared risk loci for amyotrophic lat-

eral sclerosis and frontotemporal demen-

tia: a genome-wide meta-analysis. Ann

Neurol 2014; 76: 120-33.

26. Fogh I, Lin K, Tiloca C, et al. Associa-

tion of a locus in the CAMTA1 gene with

survival in patients with sporadic amyo-

trophic lateral sclerosis. JAMA Neurol

2016; 73: 812-20.

27. Cooper-Knock J, Shaw PJ, Kirby J. The

widening spectrum of C9ORF72-related

disease; genotype/phenotype correlations

and potential modifiers of clinical phe-

notype. Acta Neuropathol 2014; 127: 333-

45.

28. Conte A, Lattante S, Zollino M, et al.

P525L FUS mutation is consistently asso-

ciated with a severe form of juvenile amy-

otrophic lateral sclerosis. Neuromuscul

Disord 2012; 22: 73-5.

29. Wu CH, Fallini C, Ticozzi N, et al. Mu-

tations in the profilin 1 gene cause famil-

ial amyotrophic lateral sclerosis. Nature

2012; 488: 499-503.

30. Cudkowicz ME, McKenna-Yasek D,

Sapp PE, et al. Epidemiology of mutations

in superoxide dismutase in amyotrophic

lateral sclerosis. Ann Neurol 1997; 41: 210-

21.

31. Winter SM, Claus A, Oberwittler C,

Völkel H, Wenzler S, Ludolph AC. Reces-

sively inherited amyotrophic lateral scle-

rosis: a Germany family with the D90A

CuZn-SOD mutation. J Neurol 2000; 247:

783-6.

32. Lacomblez L, Doppler V, Beucler I,

et al. APOE: a potential marker of disease

progression in ALS. Neurology 2002; 58:

1112-4.

33. Van Hoecke A, Schoonaert L, Lem-

mens R, et al. EPHA4 is a disease modi-

fier of amyotrophic lateral sclerosis in

animal models and in humans. Nat Med

2012; 18: 1418-22.

34. Al-Chalabi A, Calvo A, Chio A, et al.

Analysis of amyotrophic lateral sclerosis

as a multistep process: a population-

based modelling study. Lancet Neurol

2014; 13: 1108-13.

35. Watts GD, Thomasova D, Ramdeen

SK, et al. Novel VCP mutations in inclu-

sion body myopathy associated with Paget

disease of bone and frontotemporal de-

mentia. Clin Genet 2007; 72: 420-6.

36. Maruyama H, Morino H, Ito H, et al.

Mutations of optineurin in amyotrophic

lateral sclerosis. Nature 2010; 465: 223-6.

37. Cirulli ET, Lasseigne BN, Petrovski S,

et al. Exome sequencing in amyotrophic

lateral sclerosis identifies risk genes and

pathways. Science 2015; 347: 1436-41.

38. Freischmidt A, Wieland T, Richter B,

et al. Haploinsufficiency of TBK1 causes

familial ALS and fronto-temporal demen-

tia. Nat Neurosci 2015; 18: 631-6.

39. Pottier C, Bieniek KF, Finch N, et al.

Whole-genome sequencing reveals impor-

tant role for TBK1 and OPTN mutations

in frontotemporal lobar degeneration with-

out motor neuron disease. Acta Neuro-

pathol 2015; 130: 77-92.

40. Fecto F, Yan J, Vemula SP, et al.

SQSTM1 mutations in familial and spo-

radic amyotrophic lateral sclerosis. Arch

Neurol 2011; 68: 1440-6.

41. Sreedharan J, Blair IP, Tripathi VB,

et al. TDP-43 mutations in familial and

sporadic amyotrophic lateral sclerosis.

Science 2008; 319: 1668-72.

42. Kwiatkowski TJ Jr, Bosco DA, Leclerc

AL, et al. Mutations in the FUS/TLS gene

on chromosome 16 cause familial amyo-

trophic lateral sclerosis. Science 2009; 323:

1205-8.

43. Vance C, Rogelj B, Hortobágyi T, et al.

Mutations in FUS, an RNA processing pro-

tein, cause familial amyotrophic lateral

sclerosis type 6. Science 2009; 323: 1208-11.

44. Kim HJ, Kim NC, Wang YD, et al. Muta-

tions in prion-like domains in hnRNPA2B1

and hnRNPA1 cause multisystem pro-

teinopathy and ALS. Nature 2013; 495: 467-

73.

45. Bosco DA, Lemay N, Ko HK, et al. Mu-

tant FUS proteins that cause amyotrophic

lateral sclerosis incorporate into stress

granules. Hum Mol Genet 2010; 19: 4160-

75.

46. Li YR, King OD, Shorter J, Gitler AD.

Stress granules as crucibles of ALS patho-

genesis. J Cell Biol 2013; 201: 361-72.

47. Hyman AA, Weber CA, Jülicher F.

Liquid-liquid phase separation in biology.

Annu Rev Cell Dev Biol 2014; 30: 39-58.

48. DeJesus-Hernandez M, Mackenzie IR,

Boeve BF, et al. Expanded GGGGCC hexa-

nucleotide repeat in noncoding region of

C9ORF72 causes chromosome 9p-linked

FTD and ALS. Neuron 2011; 72: 245-56.

49. Renton AE, Majounie E, Waite A, et al.

A hexanucleotide repeat expansion in

C9ORF72 is the cause of chromosome

9p21-linked ALS-FTD. Neuron 2011; 72:

257-68.

50. Gijselinck I, Van Langenhove T, van

der Zee J, et al. A C9orf72 promoter repeat

expansion in a Flanders-Belgian cohort

with disorders of the frontotemporal lo-

bar degeneration-amyotrophic lateral scle-

rosis spectrum: a gene identification study.

Lancet Neurol 2012; 11: 54-65.

51. Freibaum BD, Lu Y, Lopez-Gonzalez

R, et al. GGGGCC repeat expansion in

C9orf72 compromises nucleocytoplasmic

transport. Nature 2015; 525: 129-33.

52. Zhang K, Donnelly CJ, Haeusler AR, et

al. The C9orf72 repeat expansion disrupts

nucleocytoplasmic transport. Nature 2015;

525: 56-61.

53. Donnelly CJ, Zhang PW, Pham JT, et al.

RNA toxicity from the ALS/FTD C9ORF72

expansion is mitigated by antisense inter-

vention. Neuron 2013; 80: 415-28.

54. Lagier-Tourenne C, Baughn M, Rigo F,

et al. Targeted degradation of sense and

antisense C9orf72 RNA foci as therapy for

ALS and frontotemporal degeneration.

Proc Natl Acad Sci U S A 2013; 110: E4530-

E4539.

55. Sareen D, O’Rourke JG, Meera P, et al.

Targeting RNA foci in iPSC-derived mo-

tor neurons from ALS patients with a

C9ORF72 repeat expansion. Sci Transl

Med 2013; 5: 208ra149.

56. O’Rourke JG, Bogdanik L, Muhammad

AK, et al. C9orf72 BAC transgenic mice

display typical pathologic features of ALS/

FTD. Neuron 2015; 88: 892-901.

57. Peters OM, Cabrera GT, Tran H, et al.

Human C9ORF72 hexanucleotide expan-

sion reproduces RNA foci and dipeptide

repeat proteins but not neurodegenera-

tion in BAC transgenic mice. Neuron 2015;

88: 902-9.

58. Jiang J, Zhu Q, Gendron TF, et al.

Gain of toxicity from ALS/FTD-linked re-

peat expansions in C9ORF72 is alleviated

by antisense oligonucleotides targeting

GGGGCC-containing RNAs. Neuron 2016;

90: 535-50.

59. Liu Y, Pattamatta A, Zu T, et al.

C9orf72 BAC mouse model with motor

deficits and neurodegenerative features of

ALS/FTD. Neuron 2016; 90: 521-34.

60. Puls I, Jonnakuty C, LaMonte BH, et al.

Mutant dynactin in motor neuron disease.

Nat Genet 2003; 33: 455-6.

61. Pensato V, Tiloca C, Corrado L, et al.

TUBA4A gene analysis in sporadic amyo-

trophic lateral sclerosis: identification of

novel mutations. J Neurol 2015; 262: 1376-8.

62. Al-Chalabi A, Fang F, Hanby MF, et al.

An estimate of amyotrophic lateral sclero-

sis heritability using twin data. J Neurol

Neurosurg Psychiatry 2010; 81: 1324-6.

63. Elden AC, Kim HJ, Hart MP, et al.

Ataxin-2 intermediate-length polyglutamine

expansions are associated with increased

risk for ALS. Nature 2010; 466: 1069-75.

64. Al-Chalabi A, Lewis CM. Modelling

the effects of penetrance and family size

on rates of sporadic and familial disease.

Hum Hered 2011; 71: 281-8.

65. van Blitterswijk M, van Es MA, Hen-

nekam EA, et al. Evidence for an oligo-

genic basis of amyotrophic lateral sclero-

sis. Hum Mol Genet 2012; 21: 3776-84.

66. van Rheenen W, Shatunov A, Dekker

AM, et al. Genome-wide association analy-

ses identify new risk variants and the ge-

netic architecture of amyotrophic lateral

sclerosis. Nat Genet 2016; 48: 1043-8.

67. Calvo A, Canosa A, Bertuzzo D, et al.

Influence of cigarette smoking on ALS out-

come: a population-based study. J Neurol

Neurosurg Psychiatry 2016; 87: 1229-33.





68. Lacorte E, Ferrigno L, Leoncini E,

Corbo M, Boccia S, Vanacore N. Physical

activity, and physical activity related to

sports, leisure and occupational activity

as risk factors for ALS: a systematic review.

Neurosci Biobehav Rev 2016; 66: 61-79.

69. Al-Chalabi A, Hardiman O. The epi-

demiology of ALS: a conspiracy of genes,

environment and time. Nat Rev Neurol

2013; 9: 617-28.

70. Ingre C, Roos PM, Piehl F, Kamel F,

Fang F. Risk factors for amyotrophic lat-

eral sclerosis. Clin Epidemiol 2015; 7:

181-93.

71. Weisskopf MG, O’Reilly EJ, McCul-

lough ML, et al. Prospective study of mili-

tary service and mortality from ALS. Neu-

rology 2005; 64: 32-7.

72. Beard JD, Engel LS, Richardson DB, et

al. Military service, deployments, and ex-

posures in relation to amyotrophic lateral

sclerosis etiology. Environ Int 2016; 91:

104-15.

73. Wang H, O’Reilly EJ, Weisskopf MG,

et al. Smoking and risk of amyotrophic

lateral sclerosis: a pooled analysis of 5 pro-

spective cohorts. Arch Neurol 2011; 68:

207-13.

74. McCormick AL, Brown RH Jr, Cudko-

wicz ME, Al-Chalabi A, Garson JA. Quan-

tification of reverse transcriptase in ALS

and elimination of a novel retroviral can-

didate. Neurology 2008; 70: 278-83.

75. Li W, Lee MH, Henderson L, et al. Hu-

man endogenous retrovirus-K contributes

to motor neuron disease. Sci Transl Med

2015; 7: 307ra153.

76. Seals RM, Hansen J, Gredal O, Weiss-

kopf MG. Physical trauma and amyotrophic

lateral sclerosis: a population-based study

using Danish national registries. Am J Epi-

demiol 2016; 183: 294-301.

77. Wang MD, Little J, Gomes J, Cashman

NR, Krewski D. Identification of risk fac-

tors associated with onset and progres-

sion of amyotrophic lateral sclerosis us-

ing systematic review and meta-analysis.

Neurotoxicology 2016 July 1 (Epub ahead

of print).

78. McKee AC, Stein TD, Kiernan PT, Al-

varez VE. The neuropathology of chronic

traumatic encephalopathy. Brain Pathol

2015; 25: 350-64.

79. Bensimon G, Lacomblez L, Meininger

V, ALS/Riluzole Study Group. A controlled

trial of riluzole in amyotrophic lateral

sclerosis. N Engl J Med 1994; 330: 585-91.

80. Beghi E, Chiò A, Couratier P, et al.

The epidemiology and treatment of ALS:

focus on the heterogeneity of the disease

and critical appraisal of therapeutic trials.

Amyotroph Lateral Scler 2011; 12: 1-10.

81. Nicholson KA, Cudkowicz ME, Berry

JD. Clinical trial designs in amyotrophic

lateral sclerosis: does one design fit all?

Neurotherapeutics 2015; 12: 376-83.

82. Cudkowicz ME, van den Berg LH,

Shefner JM, et al. Dexpramipexole versus

placebo for patients with amyotrophic lat-

eral sclerosis (EMPOWER): a randomised,

double-blind, phase 3 trial. Lancet Neurol

2013; 12: 1059-67.

83. Glass JD, Hertzberg VS, Boulis NM,

et al. Transplantation of spinal cord-derived

neural stem cells for ALS: analysis of

phase 1 and 2 trials. Neurology 2016; 87:

392-400.

84. Ralph GS, Radcliffe PA, Day DM, et al.

Silencing mutant SOD1 using RNAi pro-

tects against neurodegeneration and ex-

tends survival in an ALS model. Nat Med

2005; 11: 429-33.

85. Stoica L, Todeasa SH, Cabrera GT, et al.

Adeno-associated virus-delivered artificial

microRNA extends survival and delays

paralysis in an amyotrophic lateral sclero-

sis mouse model. Ann Neurol 2016; 79:

687-700.

86. Smith RA, Miller TM, Yamanaka K, et

al. Antisense oligonucleotide therapy for

neurodegenerative disease. J Clin Invest

2006; 116: 2290-6.

87. Miller TM, Pestronk A, David W, et al.

An antisense oligonucleotide against SOD1

delivered intrathecally for patients with

SOD1 familial amyotrophic lateral sclero-

sis: a phase 1, randomised, first-in-man

study. Lancet Neurol 2013; 12: 435-42.

Copyright © 2017 Massachusetts Medical Society.

IMAGES IN CLINICAL MEDICINE

The Journal welcomes consideration of new submissions for Images in Clinical

Medicine. Instructions for authors and procedures for submissions can be found

on the Journal’s website at NEJM.org. At the discretion of the editor, images that

are accepted for publication may appear in the print version of the Journal,

the electronic version, or both.



Date post:	21-Aug-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

Amyotrophic Lateral Sclerosis€¦ · right calf and hyperreflexia of the right biceps and of deep...

Documents